Mice have triumphed as the in vivo experimental model system of choice in biomedical research. However, there are clear limitations to mouse models. The literature is full of therapeutic approaches that worked in mice but failed in humans. Further, mice often provide less than optimal mimics of the human diseases being modeled, atherosclerosis being a prime example. Compared to humans, mice are very resistant to atherosclerosis. In part, this is thought to be due to fundamental differences in lipoprotein metabolism between species. Available mouse models are thus based on dietary or genetic perturbations in lipoprotein metabolism; all have drawbacks. While mouse models have provided important insights into pathogenesis, fundamental biological and practical problems with available models have hindered translation of principles derived from mouse studies to human disease. As with other difficult-to-model diseases, this has been presumed to be due to basic biological differences between species. Indeed, mice are not humans. However, data strongly suggest that the environmental conditions ubiquitously employed in mouse husbandry impair our ability to model atherosclerosis in mice. The studies in this exploratory/developmental proposal address the novel hypothesis that the severe cold stress that laboratory mice are ubiquitously subjected to (a practical paradigm employed systematically for nonscientific reasons - the comfort of their clothed human handlers) profoundly affects mouse physiology and immunology in ways that directly impair the modeling of atherosclerosis in mice. Notably, the adaptive response to cold stress involves sustained activation of the sympathetic nervous system and glucocorticoid production, both of which potently suppress the activation of macrophages-cells critical to disease pathogenesis at all stages of atherosclerosis. Furthermore, housing mice in the absence of cold stress has been reported to humanize their plasma lipoprotein profiles. The studies in this will thus directly and rapidly test the hypothesis- one strongly supported by data available in the literature - that current mouse models of atherosclerosis are undermined, fundamentally, by the chronic cold stress associated with standard mouse housing conditions. If the hypothesis is correct, this proposal has a clear, important deliverable-the development of a tractable, humanized mouse model of atherosclerosis that would provide a critically needed novel tool for research into atherosclerosis biology and therapy. PUBLIC HEALTH RELEVANCE: Laboratory mice are central to the biomedical research enterprise. This proposal seeks to develop dramatically better mouse models of human atherosclerosis by altering a key, ignored environmental variable: temperature. We hypothesize that the cold stress that laboratory mice are ubiquitously subjected to (for largely non-scientific reasons) impairs the modeling of human atherosclerotic disease in mice. The development of a tractable, humanized mouse model of atherosclerosis would provide a critically needed novel tool for research into atherosclerosis biology and therapy.